Methods and compositions for improving the feed intake of meat producing animals

ABSTRACT

New methods and compositions for inducing polyphagia in immature, meat producing animals are described utilizing certain dibenz(b,f)azepines as active ingredients. Particularly useful ingredients are 10,11-dihydro-5-H-dibenz(b,f)azepine and 5-Hdibenz(b,f)azepine.

United States Patent Baile et al.

[ METHODS AND COMPOSITIONS FOR IMPROVING THE FEED INTAKE OF MEAT PRODUCING ANIMALS [75] Inventors: Clifton A. Baile, Glen Mills; Carol Lynn McLaughlin, Malvern; Robert Lee Webb, West Chester, all of Pa.

[73] Assignee: Smithkline Corporation,

Philadelphia, Pa.

UNITED STATES PATENTS 3,126,373 3/1964 Craig .,424/244X [11] 3,812,255 May 21, 1974 6/l970 Biel ..424/244 l2/l972 Grunwaldt ..424/244 Primary Examiner-Albert T. Meyers Assistant Examiner--Frederick E. Waddell Attorney, Agent, or FirmWilliam H. Edgerton; Richard D. Foggio [57] ABSTRACT New methods and compositions for inducing polyphagia in immature, meat producing animals are described utilizing certain dibenz[b,f]azepines as active ingredients. Particularly useful ingredients are l0,l ldihydro-5-H-dibenz[b,f]azepine and 5-H- dibenz[b,f]a zepine.

10 Claims, No Drawings This invention relates to novel methods of inducing polyphagia in immature meat producing animals, such as pigs, sheep and cattle, and certain compositions useful in these new methods. More specifically, the novel methods of this invention comprise the internal preferably parenteral administration of a dibenzazepine compound to the young, preferably ruminant, animal to stimulate the animal to continue eating past its normal level of satiety thereby causing the animal to gain weight at a faster rate than that of an untreated animal. Using this invention, the meat producing animal will reach the normal market weight faster with a saving of feed, lot or pen space and labor cost. Overall, a better production efficiency and profit margin is realized by the feed lot industry by obtaining a lower feed and management cost per unit of marketable product. Also included in this invention are compositions for administration to the growing animals which aresubjeets of these methods. These veterinary compositions are comprised mainly of three groups. First, the claimed compositions may be pellets which are implanted in the animal, preferably intramuscularly, thereafter allowing release of the active dibenzazepine ingredient gradually over a period of from several days up to six months for prolonged polyphagia. This'form of administration is convenient because of the relatively low effective doses ,of certain of these active ingredients. Next, veterinary compositions comprising solutions or suspensions which can be injected into the subject animal, preferably intramuscularly. The active ingredient is present in such compositions in a quantity which is sufficient to give a positive polyphagic effect but which does not have toxic side effects or the central nervous system effects commonly associated with certain dibenzazepines.

The third category of composition is a feed composition containing an effective polyphagic but nontoxic quantity of a dibenzazepine active ingredient distributed uniformly throughout an animal feed carrier. Generally speaking the dose levels in feed compositions are higher on a per day basis than those administered by injection or implantation. All these compositions therefore comprise a veterinary carrier, pharmaceutical or feed stuff, combined with an effective, nontoxic quantity of a dibenzazepine dispersed therein.

The methods of this invention are carried out by administering the compositions described above to the immature meat producing animal internally as is convenient to the grower, that is by injection, implantation or orally such as by addition to feed, in effective but nontoxic quantities;

The basis of this invention is the unexpected discovery that commercially important animals, e.g., meat producing ruminants, when administered certain chemical ingredients of the dibenzazepine family, continue to eat past their usual point of satiety. The polyphagic effects realized are found at relatively low concentrations of the active ingredient compared to those dosage unit quantities which the N-substituted dibenzazepines elicit frank or general CNS pharmacological activity, eg ataractic, antiemetic or anticonvulsant effects in the human subjects in which they are commonly used.

2 More specifically the dibenzazepine compounds which are the active ingredients of the methods and compositions of this invention are illustrated by the following structural formula:

in which A and/or B are hydrogen, halo such as chloro or bromo or another trivial substituent known to this art such as methoxy, ethoxy, trifluoromethyl, methyl, ethyl, etc.; R is hydrogen, lower acyl such as carbamyl or diloweralkylamino alkanoyl, alkyl of l-8 carbons, diloweralkylaminopropyl or ethyl; lower alkylaminopropyl or ethyl, said lower alkyl or acyl groups having from a maximum of 8carbons, preferably for the lower alkyl groups l-2 carbons; and represents an optional double bond.

The polyphagia which is the result of this invention has been found to be general for this particular class of compounds rather than specifically or critically dependent in any substituent on the dibenzazepine ring. Therefore the chemical costs of the active ingredient being critical to saving for the lot operator, the preferred compounds are those in which A, B and R are all hydrogen or an alternative inexpensive substituent.

The above compounds can be used per se or as their salts with nontoxic acids if a basic center is present. The salts are prepared by conventional methods such as reacting the base with the calculated amount of acid depending on the number of basic centers of the base in an inorganic solvent or by double decomposition of appropriate salts. Exemplaryof such acids are the mineral acids such as hydrochloric, sulfuric, sulfamic, phosphoric, hydrobromic or nitric acids or the organic acids such as maleic, pamoic, methanesulfonic or the resin acids. The preferred parent compounds (R is H) do not form salts and must therefore be used in an injectable solvent such as dimethylformamide, dimethylacetamide or dimethylsulfoxide or an aqueous suspension of a finely micronized powder.

The dibenzazepines which are the active ingredients of this invention are old compounds or are easily prepared by procedures known to'the art. Exemplary of these procedures are those in U.S. Pat. Nos. 2,666,051; 2,667,596; 2,762,796; 2,764,580; 2,554,736; 2,948,718; 3,062,222; 3,126,373; 3,074,931. As far as we know the only dibenzazepines of Formula 1 known to be of practical use in the human pharmaceutical field are the following: carbarnazepine (an anticonvulsant used at 200-1 ,200 mg./day), desipramine (an antidepressant used at mg./day) and imipramine (an antidepressant used at 50-150 mgJday). All these are listed in the Merck Index, 8th Ed. As far as we know none of these has been used chronically for veterinary purposes especially in immature meat producing animals. And we know of no prior art disclosure of the polyphagic effects of these three compounds.

We are also aware of no human or veterinary medicinal use of the parent dibenzoazepines, ie those in which R is hydrogen especially the preferred 5-H- dibenz[b,f]azepine and dibenz[b,f]azepine.

The active ingredients were tested in groups of sheep or cattle weighing 50-60 and 200-300 kg, respectively. Feed and water were available ad libitum.

A control of dimethylsulfoxide (DMS) was maintained. The procedure comprised; 60 min. weigh feed, min. inject chemical in 1.5 ml. DMS for sheep and 5.0 ml. for cattle intravenously then weigh feed,

10,1 l-dihydro-S-H- 30 min. weigh feed, 60 min. weigh feed and 120 minwe h feast...

FEED INTAKES OF SHEEP FOLLOWING INTRAVENOUS lNJECTlONS Chemical Dose n Cumulative Intake (g) Control sheep min min 120 min Code 20 mg 8 89:19" 102:17* 106:16* A A 40 mg 8 92 :15** 107 :14* 121 16* do. mg 8 18" 105:25* 111:25 do.

20 mg 8 77:16* 79:16 81:16 A B 40 mg 7 1l1:12** 122 9.9" 130 :13 do. 80 mg. 8 112:20 131 :26" 138:24 do. 120 mg 7 129:15 141:17" 142:17** do.

C 16 mg 8 :21 99:24 113:27 A

10 mg 8 88:18 93:16* 1l3:15* A D 20 mg 7 :16 112:l6** 117:18* do. 40 mg 8 :20" 122:22 124:22* (10.

E 40 mg 8 105: 10 129: 15 :14" A 80 mg 8 64:41 78 :46 139 :54 do.

97 pig 8 64 26 69 25 85 29 A g 8 41:12 42:12 67:24 do. 310 pg 8 78:13 80:13 93:13 do. F 620 pg 8 57:17 59:17 66:17 do.

1.25 mg 8 54:15 63:14 85:12 do. 50 mg 8 43:11 43:11 43:1l* do. 20 mg 8 6.3 2.9 6.3 2.9* 23 6.0 do.

155 pg 8 36:11 63:13 88:17 B G 310 ag 8 71:14 79:13 [12:16 do. 620 pg 8 46:12 49:14 51:15 do.

310 pg 8 49:13 50:13 64:15 B H 620 #g 8 70 9.7 95 17* 122 20* do. 1.24 mg 8 66 :14* 70 :14 74 :13 do.

Control 21 43:12 53: 14 69:17 A 24 47 9.7 62 6.3 84 8.2 B

The asterisks denote particularly significant figures over the coded controls.

FEED INTAKES OF CATTLE FOLLOWING INTRAVENOUS INJECTIONS Chemical Dose n Cumulative Intake (kg) Control cattle 30 min 60 min 120 min Code 50 mg 7 .03 .01 .26 .09 .35 .10 A A 100 mg 7 .21 07* .75 .12" 1.36 .20 B 200 mg 8 .03 .01 .06 .02 .25 .05 A

B 100mg 7 .13-1'.08 .41+.l7 1.06+.27* B D 100 mg 8 .07 .02 .37 .09* .67 .15 A

Control 32 .07 .02 .16.+ .03 .32 .04 A 31 .06+.02 .18+.05 .46+.10 B

3-chloro-5-(3-methylaminopropy1)- implants. The amount of the active ingredient in the compositions will be a quantity of the dibenzazepine 60 sufficient to induce polyphagia in the satiated immature animal but not be overtly toxic or pharmacodynamic in the animal.

The animal feeds most generallyused in conjunction with the method of this invention are either various 65 grain mixtures and/or roughage feeds such as hay commonly fed to growing ruminant animals such as cattle or sheep. The amount of additive used to supplement such feeds will be in an amount sufficient to increase feed intake and/or improve the feed efficiency of the' animal but not to have a toxic or noxious effect; in the broad range of from about mg. to about 2,000 g. per ton of feed, preferably from about 1 to about 200 g. per ton. An average sheep will ingest about 3-4 lbs. of feed daily; an average feed lot steer about 25 lbs. The preferable broad range of dosage for ruminants by parenteral administration is approximately 10 rag. to 20 g. per day preferably about 1 mg. to 2 g. The compositions will therefore contain multiples of this figure depending on the number of days of duration of activity which are desired.

Generally the methods of this invention using parenteral administration comprise injecting, subcutaneously, intramuscularly or intravenously, a polyphagic but nontoxic amount of the active ingredient such as the daily dosage quantities mentioned above which are based on the activity of the most preferred compounds. Administration may be usually at most once a day but may be varied as polyphagia is desired. Usually the treatmentmay take place every several days, weeks or even months. The implant forms of the invention might be used only onc-to'three or four times in the growing time of the animal. One implant is preferable. They might be administered in the ear or bind quarter of the animal.

For commercial use, the active ingredients when used in the feed can be readily used as premix formulations in which the chemical is distributed uniformly throughout a standard animal feed carrier. This premix or concentrate is then mixed with a normal diet for the animal desired. Examples of such carriers are soybean meal, corn oil, ground corn, barley, wheat, corn gluten meal, corn distillers solubles, soyflour mineral mixtures such as vermiculite and diatomaceous earth. The active EXAMPLE 1 Ingredients Weight per cent Mixed hay 40.0 Ground yellow corn 45.0 Soybean oil meal 7.0 Cane molasses 7.0 Decalcium phosphate 0.5 Trace minerals salt .5 Vitamin A 300 l.U./lb. Vitamin D [50 l.U./lb. Dibenzazepine The method of this invention using feed compositions comprises allowing the growing animal to graze or be fed ad libitumon the supplemented rations or to be fed on aregular schedule.

EXAMPLE 2 Ingredients Weight per cent Dihydrodibenzazepine 50 mg. Calcium sulfate, dihydrate 20 mg. Gelatin 4 mg. Magnesium stearate l mg. Talc 2 mg.

The dihydrodibenzazepine and calcium sulfate, dihydrate are mixed and passed through a No. 40 standard mesh screen. The screened mixture is then granulated with hot 15% gelatin solution, screened through a No. 10 mesh screen and dried overnight at F. The granules are again screened through a No. 40 mesh screen and mixed with the magnesium stearate and tale. The granulesarc compressed into implants using a Vs inch flat face punch and die. One implant is administered intramuscularly. Other standard methods of preparing and using implants are described in US. Pat. No. 3,428,729 and the references contained therein as well as in J. Animal Science, 27, 1772' (1968) or J. Biomed. Mater. Res., 1, 433 (1967).

What we claim is:

l. The method of inducing poly'phagia in immature, meat producing animals selected from the group consisting of pigs, sheep and cattle comprising administering internally to said animals an effective polyphagia inducing amount but nontoxic quantity of a compound having the formula:

the. form la.-.

3. The method of claim 1 in which the compound has the female; t

4. The method of claim 1 in which the compound is administered to a ruminant animal.

5; The method of claim 4 in which the compound is administered to the animal in the form of an implant.

6. The method of claim 4in which the quantity of the 291992 9 isframa g ins-.2 2 Pe x 7 8 7. A veterinary composition having polyphag C aCti 8. The composition of claim 7 in which the composiity comprising a veterinary carrier and as an active intion is in the form of a veterinary implant. gredient dispersed in said carrier a dibenzazepine com- 9. The composition of claim 7 in the form of a premix pound in a quantity sufficient to induce polyphag c C- comprising l-75 percent by weight of the dibenzazetivity in an immature meatproducing animal but not to pine.

be toxic to the animal, said compound being dibenzaze- 10. The composition of claim 7 comprising 10mg to pine or 10,1l-dihydrodibenzazepine and said carrier about 2,000g per ton of animal feed.

being an animalfeed or implant. n, V .2 i.-. 

2. The method of claim 1 in which the compound has the formula:
 3. The method of claim 1 in which the compound has the formula:
 4. The method of claim 1 in which the compound is administered to a ruminant animal.
 5. The method of claim 4 in which the compound is administered to the animal in the form of an implant.
 6. The method of claim 4 in which the quantity of the compound is from about 1 mg. to 2 g. per day.
 7. A veterinary composition having polyphagic activity comprising a veterinary carrier and as an active ingredient dispersed in said carrier a dibenzazepine compound in a quantity sufficient to induce polyphagic activity in an immature meat producing animal but not to be toxic to the animal, said compound being dibenzazepine or 10,11-dihydrodibenzazepine and said carrier being an animal feed or implant.
 8. The composition of claim 7 in which the composition is in the form of a veterinary implant.
 9. The composition of claim 7 in the form of a premix comprising 1-75 percent by weight of the dibenzazepine.
 10. The composition of claim 7 comprising 10mg to about 2,000g per ton of animal feed. 